Oil soluble esters of phenylthioarsonites



Patented July 30, 1940 UNITED 's-TATEs PATENT OFFICE OIL SOL Arthur James Ewins,

UBLE ESTERS 0F PHENYL- THIOARSONITES Romford, and George Newbery,Hutton, England, assignors to May &

Baker, Limited, Land of Great .Britain No Drawing. Application May 4,1937, Serial No.

on, England, a company a 140,602. In Great Britain May 9, 1936 4 Claims.The present invention relates to therapeutical- Therapeutically activeorganic com active organic compounds of arsenic.

pounds of arsenic have hitherto been employed exclusively 5 in aqueoussolution..,.Such-solutions are for the, most part injectedintravenously, which results in averyr apid elimination of the greaterpart of the drug injected, thereby reducing its potential efficacy. Inthe comparatively few cases in which such solutions are em intramuscularinjection, though slower than in th elimination is ployed' bysubcutaneous or also rapid e first-mentioned method of administration.In the case of organic compounds of bismuth the employment of prep-'arations soluble in oily media has shown itself to be of value as ameans of obtaining moderately slow absorption and prolonged therapeuticefiect and of administering products which it would'be otherwise toemploy as therapeutic impossible agents. i

The object of the tain oil which have therapeutic possibilities in mentof diseases such as syphilis and According to this invention suchpresentinvention is to obsoluble organic compounds of arsenic thetreatyaws. oil-soluble organiccompounds of arsenic may be obtainedby'the condensati arsenoxidesor hydroxyl, amino stituents in the a ofmercapto ac derivative, thiomalic acid, such dibutyl mercapto-succinateHS-CHCOOC4H9 omoooc n on of ar ylor substit ryl nucleus with aliph Inorder to obtain the resulting comp contain a total of that the use ofthe and the methyl to is not included in methyl ester of thio thisinventi uted aryl- -dihalogen ar'sines containing or acetylamino groupsas subatic esters etic acid or "its a-substituted for example, as

sufiicient solubility in oil in ound, the ester used should more than 6carbon atoms so malic acid butyl esters of thiolacetio acid on. Theresulting products which may be represented by the general formula R-Asin which R represents a member comprising an aryl or substituted and Rwhich in ay contain substituent groups acterised by their solubility innon-h solvents, e. g. benzene, chloroform, at

particular by their solubility in vegeta the group aryl radical is anester of a carboxyl-alkyl-radicle are charydroxylic c. and in ble oilsor other esters suitable as m use by injection.

The following examples illustrate how the invention may be carried outin practice, but it is'to be understood that the invention is in no waylimited to the details given in these examples: Example 1 edia fortherapeutic sisted of bis-(carboamido phenyl thioarsowas readily solublein or ethyl oleate.

s-om-ooooniu ganic solvents and in v Example 2 60 grams of3-acetamldo-4-hydroxyphenyl arsenoxide were suspended in a mixture ofgrams of dibutyl mercaptosuccinic ester and 300 cc.- of ethyl alcohol.Solution was obtained as before and an oil separated on the addition ofwater. taken up in benzene. The benzene solution after being dried andevaporated yielded the required bis(1,2-di(carbobutoxy)ethyl-3'acetamido 4' hydroxy phenyl thioarsonite HOQAs-S-ZH-OOOCLED as aslightly yellow viscous oil readily soluble in organic solvents andsoluble to a considerable extent in olive oil,

Example 3 200 grams of 2-hydroxy-4-acetamido arsenoxide were added to amixture of 50 of butylmercaptosuccinate dissolved in 1 absolute alcohol.The resulting solution tered and diluted with an equal volume 0 gramslitre of was filof water.

Theoil was washed with dilute spirit and 35 -phenyl The oil whichseparated was taken up in chloroform, washed with 50% spirit to removeexcess of unchanged ester and finally with water. The chloroformsolution was dried over anhydrous sodium sulphate and on removal ofsolvent the required bis 1,21- di(carbobuto xy) ethyl) 4"acetamido-2"-hydroxyphenyl thioarsonite orb-00004119 CH3. o .NH-QASreadily soluble in organic solvents. This oil may be dissolved in ethyloleate-orothersuitable solvent for use therapeutically by injection.

Example 4 100 grams of 2-hydroxy-5-acetamido-phenylarsenoxide weredissolved in a mixture of 250 cc. dibutyl'mercapto succinic ester and500 cc. absolute alcohol, with slight warming if necessary, and the oilyproduct thrown out by the addition of a littlewater. The oily productwas dissolved in chloroform and the solution dried over anhydrous sodiumsulphate. On' evaporation of the solvent bis 1,2-di(carbobutoxy) ethyl)-acetamide 2' hydroxy phenylthioarsonite CHr-C 0 0 Q4110 S-CB'r-C O OC4119 s -on-oo 0 04m GHQ-'0 O 0 04110.

remained as a nearly colourless oil readily soluble in organic solvents,in ethyl oleate and to a lesser a; degree in certain natural vegetableoils such, for

" example, as chaulmoogra oil.

Example 5 300- grams of 2-hydro y-5 amino-phenyldi chlorarsine wereadded to 500 grams'of dibutyl mercapto succinate in a litre of absolutealcohol. Rapid solution ensued with some evolutionof heat. After a fewminutes further heating on a steam-bath, the mixture was cooled anddiluted with an equal volume of water. The lower oily layer wasseparated, taken up in chloroform and washed with dilute sodiumcarbonate solution till free from acid and finally with water till freefrom alkali. The chloroform solution 55? was then dried over anhydroussodium sulphate,

and the solvent removed when the required bis remained as a colourlessoil, insoluble in water but (1,2-di(carbobutoxy) ethyl) 5-amino2-hydroxyphenylthioarsonite 0111-0 0 o 0.110 NH:

remained as a yellow oil which was readily solu- 2. The oil-soluble,arsenic compound bis(1,2-di (carbobutoxy)ethyl)4' acetamido. 2" hydroxyphenyl thioarsonite r omooNHOAs 3. The, oil-soluble arsenic compoundbis(l,2 -di (carbobutox-y), ethyl) 5'-acetamido 2hydroxyphenylthioarsonite our-000mm- S- HCOOC4H0 5 awn-000mm v HFCOOCAHQ4. The oil soluble arsenic compound bis(1',2-

di,(carbobutoxy) ethyl) -5' amino 2' hydroxyv phenylthioarsonite CHr-C O0 04K:

ARTHUR JAMES EWINS. GEORGE NEWBERY.

